ES2616432T3 - Derivatives of tricyclic alkenes as inhibitors of HIV binding - Google Patents

Abstract

A compound of Formula I, including pharmaceutically acceptable salts thereof: ** Formula ** in which A is selected from the group consisting of: ** Formula ** and in which a, b, c, d and d are selected independently among the group consisting of hydrogen, halogen, cyano, nitro, COOR56, XR57, NA1A2, C (O) R7, C (O) NR55R56, B, Q and E; B is selected from the group consisting of -C (> = NR46) (R47), C (O) NR40R41, aryl, heteroaryl, heteroalicyclic, S (O) 2R8, S (O) 2NR40R41, C (O) R7, XR8a, (C1-6) alkyl -NR40R41, (C1-6) alkyl -COOR8b; wherein said aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or one to three same or different substituents selected from the group F; wherein aryl is naphthyl or substituted phenyl; wherein heteroaryl is a mono or bicyclic system containing from 3 to 7 ring atoms for a monocyclic system and up to 12 atoms in a condensed bicyclic system, including 1 to 4 heteroatoms; wherein the heteroalicyclic is a 3- to 7-membered cyclic mono ring that may contain 1 to 2 heteroatoms in the main chain of the ring and that may be fused to a benzene or pyridine ring; Q is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl and (C2-6) alkenyl; wherein said (C1-6) alkyl and (C2-6) alkenyl are optionally substituted with one to three same or different halogens or one to three same or different substituents selected from the group consisting of C (O) NR55R56, hydroxy, cyano and XR57; E is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl and (C2-6) alkenyl; wherein said (C1-6) alkyl and (C2-6) alkenyl are, independently, optionally substituted with a member selected from the group consisting of phenyl, heteroaryl, SMe, SPh, -C (O) NR56R57, C ( O) R57, SO2-C1-6 alkyl and SO2Ph; wherein heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; F is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, aryloxy, thioalkoxy (C1-6), cyano, halogen , nitro, -C (O) R57, benzyl, -NR42C (O) -alkyl (C1-6), - NR42C (O) -cycloalkyl (C3-6), -NR42C (O) -aryl, -NR42C (O ) -heteroaryl, -NR42C (O) -heteroalicyclic, a 4, 5 or 6-membered cyclic ring N-lactam, -NR42S (O) 2-C 1-6 alkyl, -NR42S (O) 2-cycloalkyl ( C3-6), -NR42S (O) 2-aryl, - NR42S (O) 2-heteroaryl, -NR42S (O) 2-heteroalicyclic, S (O) 2-alkyl (C1-6), S (O) 2-aryl , -S (O) 2 NR42R43, NR42R43, (C1-6) alkyl -C (O) NR42R43, C (O) NR42R43, NHC (O) NR42R43, OC (O) NR42R43, NHC (O) OR54, alkyl ( C1-6) -NR42R43, COOR54 and (C1-6) alkyl -COOR54; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, (C1-6) alkoxy and aryloxy optionally are substituted with one to nine equal or different halogens or one to five substituents same or different selected from group G; in which aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; G is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, aryloxy, cyano, halogen, nitro, -C (O ) R57, benzyl, -NR48C (O) -alkyl (C1-6), -NR48C (O) - cycloalkyl (C3-6), -NR48C (O) -aryl, -NR48C (O) -heteroaryl, -NR48C ( O) -heteroalicyclic, a 4, 5 or 6-membered ring cyclic N-lactam, -NR48S (O) 2-C 1-6 alkyl, -NR48S (O) 2-cycloalkyl (C3-6), -NR48S (O) 2-aryl, - NR48S (O) 2-heteroaryl, -NR48S (O) 2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR48R49, (C1-6) alkyl - C (O) NR48R49, C (O) NR48R49, NHC (O) NR48R49, OC (O) NR48R49, NHC (O) OR54, alkyl (C1-6) -NR48R49, COOR54 and alkyl (C1-6) -COOR54; in which aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; R7 is selected from the group consisting of (C1-6) alkyl, (C2-6) alkenyl, (C3-7) cycloalkyl, aryl, heteroaryl and heteroalicyclic; wherein said aryl, heteroaryl and heteroalicyclic are optionally substituted with one to 10 three same or different halogens or with one to three same or different substituents selected from the group F; wherein for R7, R8, R8a, R8b aryl is phenyl; heteroaryl is a mono or bicyclic system that contains 3 to 7 ring atoms for monocyclic systems and even atoms in a bicyclic system, including 1 to 4 heteroatoms; wherein heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; R8 is selected from the group consisting of hydrogen, (C1-6) alkyl, cycloalkyl (C3-7), alkenyl (C2-6), cycloalkenyl (C3-7), alkynyl (C2-6), aryl, heteroaryl and heteroalicyclic; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, (C2-6) alkenyl, (C3-7) cycloalkenyl, (C2-6) alkynyl, aryl, heteroaryl and heteroalicyclic optionally is substituted with one to six equal or different halogens or one to five identical or different substituents selected from the group F or (C1-6) alkyl, cycloalkyl (C3-6), cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-) alkoxy 6), halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate , sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl; R8a is a member selected from the group consisting of aryl, heteroaryl and heteroalicyclic; wherein each member is optionally independently substituted with one to six same or different halogens or one to five same or different substituents selected from the group F; R8b is selected from the group consisting of hydrogen, (C1-6) alkyl and phenyl; X is selected from the group consisting of NH or NCH3, O and S; R40 and R41 are independently selected from the group consisting of (a) hydrogen; (b) (C1-6) alkyl or (C3-7) cycloalkyl substituted with one to three same or different halogens or one to two same or different substituents selected from the group F or different functional groups: (C1-6) alkyl , C3-6 cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, C1-6 alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfonamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine , peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl; and (c) (C1-6) alkoxy, aryl, heteroaryl or heteroalicyclic; or R40 and R41 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine and morpholine; and wherein said aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or one to two same or different substituents selected from the group F; in which for R40 and R41 aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 6 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; provided that when B is C (O) NR40R41, at least one of R40 and R41 is not selected from groups (a) or (b); R42 and R43 are independently selected from the group consisting of hydrogen, (C1-6) alkyl, allyl, (C1-6) alkoxy, (C3-7) cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R42 and R43 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine and morpholine; and wherein said (C1-6) alkyl, (C1-6) alkoxy, (C3-7) cycloalkyl, aryl, heteroaryl and heteroalicyclic acid are optionally substituted with one to three same or different halogens or one to two equal substituents or different selected from group G or different functional groups: (C1-6) alkyl, (C3-6) cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, halogen, benzyl, primary amine , secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl; in which for R42 and R43

Description

Derivatives of tricyclic alkenes as inhibitors of HIV binding

Field of the Invention

The present invention provides compounds that have pharmacological properties and that influence biology, its pharmaceutical compositions and use. In particular, the invention herein refers to derivatives of tricyclic alkenes as inhibitors of HIV binding that possess a unique antiviral activity, as well as processes for the preparation of these compounds and compositions containing these compounds.

Background of the invention

HIV-1 infection (human immunodeficiency virus 1) continues to be a major medical problem, with an estimated 45-50 million people infected in the world at the end of 2010. The number of HIV and AIDS cases (acquired immunodeficiency syndrome) has increased rapidly. In 2005, approximately 5.0 million new infections were reported and 3.1 million people died of AIDS. The drugs currently available for the treatment of HIV include the nucleoside reverse transcriptase (TI) inhibitors zidovudine (or AZT or RETROVIR®), didanosine (or VIDEX®), stavudine (or ZERIT®), lamivudine (or 3TC

or EPIVIR®), zalcitabine (or DDC or HIVID®), abacavir succinate (or ZIAGEN®), tenofovir disoproxil fumarate salt (or VIREAD®), emtricitabine (or FTC-EMTRIVA®); non-nucleoside reverse transcriptase inhibitors: nevirapine (or VIRAMUNE®), delavirdine (or RESCRIPTOR®), efavirenz (or SUSTIVA®), etravirine (INTELENCE®) and rilpivirine (EDURANT®) and peptidomimetic protease inhibitors or approved formulations: saquina , indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, KALETRA® (lopinavir and Ritonavir), darunavir, atazanavir (REYATAZ®) and tipranavir (APTIVUS®) and integrase inhibitors such as raltegravir (ISENTRESS®) and entry inhibitors such as enfuvirtide (T-20) (FUZEON®) and Maraviroc (SELZENTRY®). Several combinations of individual pills have also been approved, including COMBIVIR® (containing lamivudine and zidovudine), TRIZIVIR® (containing abacavir, zidovudine and lamivudine), EPZICOM® (containing abacavir and lamivudine), TRUVADA® (containing disoproxil fumarate of tenofovir and emtricitabine), ATRIPLA® (containing efavirenz, emtricitabine and disoproxil fumarate of tenofovir) and COMPLERA® (containing emtricitabine, rilpivirine and disoproxil fumarate of tenofovir).

Each of these drugs can only temporarily prevent viral replication if used alone. However, when used in combination, these drugs have a profound effect on viremia and disease progression. In fact, significant reductions in mortality rates among AIDS patients have been documented as a result of the widespread application of combination therapy. However, despite these impressive results, drug combination therapies can ultimately fail in 30 to 50% of patients. Insufficient drug potency, non-observance of treatment, restricted tissue penetration and specific drug limitations within certain cell types (for example, most nucleoside analogs cannot be phosphorylated at rest cells) can explain Incomplete suppression of sensitive viruses. In addition, the high rate of replication and rapid renewal of HIV-1 combined with frequent incorporation of mutations, leads to the emergence of drug resistant variants and treatment failures when suboptimal drug concentrations are present. Therefore, new anti-HIV agents with different resistance patterns and pharmacokinetics as well as favorable safety profiles are needed to provide more treatment options. Improved HIV fusion inhibitors and HIV input coreceptor antagonists are two examples of new classes of anti-HIV agents that are being further studied by a number of researchers.

HIV binding inhibitors are a new subclass of antiviral compounds that bind to the HIV surface glycoprotein, gp120, and interfere with the interaction between the gp120 surface protein and the CD4 receptor of the host cell. Therefore, they prevent HIV from binding to human CD4 T lymphocyte and block HIV replication in the first stage of the HIV life cycle. The properties of HIV binding inhibitors have been improved in an effort to obtain compounds with maximized utility and efficacy as antiviral agents. A disclosure describing indoles whose structure, shown below for BMS705, is representative, has been disclosed in US 6,469,006 (derivatives of antiviral indoloxoacetyl piperazine).

Two other compounds, named in the BMS-806 and BMS-043 literature, have been described in both the academic and patent techniques:

It should be noted that, of these three structures, a piperazin amide is present in all (in these three structures a piperazin phenyl amide) and this group is directly linked to an oxoacetyl moiety. The oxoacetyl group is linked in the 3-position of the 4-fluoro indole in BMS-705 and in the 3-position of the substituted azaindoles in BMS-806 and BMS-043.

In an effort to obtain improved anti-HIV compounds, subsequent publications described, in part, modified substitution patterns in indoles and azaindoles. Examples of such efforts include: (1) new substituted indoloxoacetic piperazine derivatives, (2) substituted piperazinylxoacetylindole derivatives and (3) substituted azaindoloxoacetic piperazine derivatives.

The replacement of these groups with other substituted or bicyclic heteroaromatic or heteroaromatic hydrocarbons has also proven feasible. Examples include: (1) indole amidopiperazine derivatives, azaindole and related heterocyclic groups; (2) antiviral bicyclo [4.4.0] derivatives; and (3) diazaindole derivatives.

A few select replacements for the piperazin amide portion of the molecules have also been described in the art and among these examples are (1) some piperidine alkenes; (2) some pyrrolidin amides; (3) some Naril or heteroaryl piperazines; (4) some piperazinyl ureas; and (5) some compounds that contain carboline.

WO 95/10516 describes tricyclic amide and urea compounds for the inhibition of abnormal cell growth. A procedure or procedures for the preparation of prodrugs for this class of compounds is disclosed in Prodrugs of Piperazine and Substituted Piperidine Antiviral Agents (Ueda et al., U.S. Patent No. 7,745,625 or WO 2005/090367 ).

A published PCT patent application WO 2003/103607 discloses a test useful for testing some HIV inhibitors.

Several published patent applications describe combination studies with piperazin benzamide inhibitors, for example, US Publication. No. 2005/0215543 (WO 2005/102391), U.S. Publication No. 2005/0215544 (WO 2005/102328) and US Pat. No. 7,776,863 (WO 2005/102392), U.S. Publication US No. 2004/18692 A1.

A publication about new compounds of this class of binding inhibitors (Wang, J. et al., Org. Biol. Chem., 3: 1781-1786 (2005)) and a patent application about some more distantly related compounds they have appeared in WO 2005/016344.

Published patent applications WO 2005/016344 and WO 2005/121094 also describe piperazine derivatives that are HIV inhibitors. Other references in the area of HIV binding include US Pat. No. 7,851,476, 7,396,830, 7,504,399, 7,348,337 and 7,354,924 and WO 2007/103456. A bibliographic reference is J. Med. Chem., 50: 6535 (2007).

5 Therefore, what is needed in the art are new HIV binding inhibitor compounds and compositions thereof, which are effective against HIV infection.

Of particular interest are new derivatives of tricyclic alkenes as HIV binding inhibitor compounds, which are described herein. The compounds of the present invention are derived from tricyclic alkenes, which are believed to be structurally distinct from piperazin aril HIV binding inhibitors.

10 amide established in the existing bibliography.

Summary of the invention

The present invention provides compounds of the Formula I below, the pharmaceutically acceptable salts and / or solvates (for example, hydrates) thereof, their pharmaceutical formulations and their use in patients suffering from or susceptible to a virus such as HIV . The compounds of Formula I, their salts and / or solvates

Pharmaceutically acceptable agents are effective antiviral agents, in particular as HIV inhibitors. They are useful for the treatment of HIV and AIDS.

An embodiment of the present invention relates to one or more compounds of Formula I, including pharmaceutically acceptable salts thereof:

20 in which A is selected from the group consisting of:

in which

25 a, b, c, d and e are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, COOR56, XR57, NA1A2, C (O) R7, C (O) NR55R56, B, Q and E;

B is selected from the group consisting of -C (= NR46) (R47), C (O) NR40R41, aryl, heteroaryl, heteroalicyclic, S (O) 2R8, S (O) 2NR40R41, C (O) R7, XR8a, (C1-6) alkyl -NR40R41, (C1-6) alkyl -COOR8b; in which said aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or of 30 one to three identical or different substituents selected from the group F; in which aryl is naphthyl or phenyl replaced; wherein heteroaryl is a mono or bicyclic system that contains 3 to 7 ring atoms for a monocyclic system and up to 12 atoms in a condensed bicyclic system, including 1 to 4 heteroatoms; wherein the heteroalicyclic is a 3- to 7-membered cyclic mono ring that may contain 1 to 2 heteroatoms in the main chain of the ring and which may be condensed with a benzene or pyridine ring;

Q is selected from the group consisting of (C1-6) alkyl, cycloalkyl (C3-7) and alkenyl (C2-6); wherein said (C1-6) alkyl and (C2-6) alkenyl are optionally substituted with one to three same or different halogens or one to three same or different substituents selected from the group consisting of C (O) NR55R56, hydroxy, cyano and XR57;

E is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl and (C2-6) alkenyl; wherein said (C1-6) alkyl and (C2-6) alkenyl are, independently, optionally substituted with a member selected from the group consisting of phenyl, heteroaryl, SMe, SPh, -C (O) NR56R57, C ( O) R57, SO2-C1-6 alkyl and SO2Ph; wherein heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms;

F is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, aryloxy, thioalkoxy (C1-6), cyano, halogen , nitro, -C (O) R57, benzyl, -NR42C (O) -alkyl (C1-6), NR42C (O) -cycloalkyl (C3-6), -NR42C (O) -aryl, -NR42C (O) -heteroaryl, -NR42C (O) -heteroalicyclic, a 4, 5 or 6-membered ring cyclic N-lactam, -NR42S (O) 2-C1-6 alkyl, -NR42S (O) 2-C3-cycloalkyl -6), -NR42S (O) 2-aryl, NR42S (O) 2-heteroaryl, -NR42S (O) 2-heteroalicyclic, S (O) 2-alkyl (C1-6), S (O) 2-aryl, - S (O) 2 NR42R43, NR42R43, (C1-6) -C (O) NR42R43, C (O) NR42R43, NHC (O) NR42R43, OC (O) NR42R43, NHC (O) OR54, alkyl (C1- 6) -NR42R43, COOR54 and (C1-6) alkyl -COOR54; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, (C1-6) alkoxy and aryloxy optionally are substituted with one to nine equal or different halogens or one to five substituents same or different selected from group G; in which aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;

G is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, aryloxy, cyano, halogen, nitro, -C (O ) R57, benzyl, -NR48C (O) -alkyl (C1-6), -NR48C (O) cycloalkyl (C3-6), -NR48C (O) -aryl, -NR48C (O) -heteroaryl, -NR48C (O ) -heteroalicyclic, a 4, 5 or 6-membered ring cyclic N-lactam, -NR48S (O) 2-C 1-6 alkyl, -NR48S (O) 2-cycloalkyl (C3-6), -NR48S ( O) 2-aryl, NR48S (O) 2-heteroaryl, -NR48S (O) 2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR48R49, alkyl (C1-6) C (O) NR48R49, C (O) NR48R49, NHC (O) NR48R49, OC (O) NR48R49, NHC (O) OR54 ', (C1-6) alkyl -NR48R49, COOR54 and (C1-6) alkyl -COOR54; in which aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;

R7 is selected from the group consisting of (C1-6) alkyl, (C2-6) alkenyl, (C3-7) cycloalkyl, aryl, heteroaryl and heteroalicyclic; wherein said aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or with one to three same or different substituents selected from the group F;

wherein for R7, R8, R8a, R8b aryl is phenyl; heteroaryl is a mono or bicyclic system that contains 3 to 7 ring atoms for monocyclic systems and up to 10 atoms in a bicyclic system, including 1 to 4 heteroatoms; wherein heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;

R8 is selected from the group consisting of hydrogen, (C1-6) alkyl, cycloalkyl (C3-7), alkenyl (C2-6), cycloalkenyl (C3-7), alkynyl (C2-6), aryl, heteroaryl and heteroalicyclic; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, (C2-6) alkenyl, (C3-7) cycloalkenyl, (C2-6) alkynyl, aryl, heteroaryl and heteroalicyclic optionally is substituted with one to six equal or different halogens or one to five identical or different substituents selected from the group F or (C1-6) alkyl, cycloalkyl (C3-6), cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-) alkoxy 6), halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate , sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl;

R8a is a member selected from the group consisting of aryl, heteroaryl and heteroalicyclic; wherein each member is optionally independently substituted with one to six same or different halogens

or from one to five identical or different substituents selected from the group F;

R8b is selected from the group consisting of hydrogen, (C1-6) alkyl and phenyl;

X is selected from the group consisting of NH or NCH3, O and S;

R40 and R41 are independently selected from the group consisting of (a) hydrogen; (b) (C1-6) alkyl or (C3-7) cycloalkyl substituted with one to three same or different halogens or one to two same or different substituents selected from the group F or different functional groups: (C1-6) alkyl , C3-6 cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, C1-6 alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfonamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, acid

phosphoric, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl; and (c) (C1-6) alkoxy, aryl, heteroaryl or heteroalicyclic; or R40 and R41 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine and morpholine; and wherein said aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or one to two same or different substituents selected from the group F; in which for R40 and R41 aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 6 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; provided that when B is C (O) NR40R41, at least one of R40 and R41 is not selected from groups (a) or (b);

R42 and R43 are independently selected from the group consisting of hydrogen, (C1-6) alkyl, allyl, (C1-6) alkoxy, (C3-7) cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R42 and R43 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine and morpholine; and wherein said (C1-6) alkyl, (C1-6) alkoxy, (C3-7) cycloalkyl, aryl, heteroaryl and heteroalicyclic acid are optionally substituted with one to three same or different halogens or one to two equal substituents or different selected from group G or different functional groups: (C1-6) alkyl, (C3-6) cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, halogen, benzyl, primary amine , secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl; in which for R42 and R43 aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 6 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;

R46 is selected from the group consisting of H, phenyl, aryl, heteroaryl and (C1-6) alkyl, OR57 and NR55R56;

R47 is selected from the group consisting of H, amino, hydroxyl, phenyl, aryl, heteroaryl and (C1-6) alkyl;

R48 and R49 are independently selected from the group consisting of hydrogen, (C1-6) alkyl, phenyl, aryl and heteroaryl;

R50 is selected from the group consisting of H, (C1-6) alkyl, (C3-6) cycloalkyl and benzyl; wherein each of said (C1-6) alkyl, (C3-7) cycloalkyl and benzyl are optionally substituted with one to three (C1-6) alkyl, (C3-6) cycloalkyl, cyano, phenyl, aryl, heteroaryl , heteroalicyclic, hydroxy, (C1-6) alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone , sulfonamide, sulfonamide, acyl sulfonamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squared acid, squaric acid, oxime, hydrazine, peroxide, equal or different, among which ether, peroxide, thioether , secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl

R54 is selected from the group consisting of hydrogen and (C1-6) alkyl;

R54 'is (C1-6) alkyl;

R55 and R56 are independently selected from the group consisting of hydrogen and (C1-6) alkyl;

and R57 is selected from the group consisting of hydrogen, (C1-6) alkyl, aryl, heteroaryl; Y

A1 and A2 are independently selected from hydrogen, (C1-6) alkyl, aryl, heteroaryl, SO2D1, SO2ND2D3, COD4, COCOD4, COOD4, COND5D6, COCOND5D6, COCOOD4, C (= ND7) D8, C (= ND9) ND10D11;

A1 and A2 can either connect to each other or join to form a ring structure;

D1, D2, D3, D4, D5, D6, D7, D8, D9, D10 and D11 are each independently selected from the group consisting of H, C1-C50 alkyl, C3-C50 cycloalkyl, C3-C50 alkenyl, cycloalkenyl C4-C50, phenyl, heteroaryl, C3-C50 amide and C3-C50 ether; heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo [4,5-b] pyridinin -yl, 1H-imidazo [4,5-c] pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,

tetrazolyl, tetrazinyl, triazinyl and triazolyl; provided that the carbon atoms comprising the carbon-carbon double bond of said C3-C20 alkenyl or the carbon-carbon triple bond of said C3-C20 alkynyl are not the point of attachment with the nitrogen to which D2 binds, D3, D5, D6, D7, D9, D10 and D11; wherein said C1-C50 alkyl, C3-C50 cycloalkyl, C3-C50 alkenyl, C4-C50 cycloalkenyl, aryl, phenyl, heteroaryl, C3-C50 amide and C3-C50 ether are optionally substituted with one to three of the following functionalities , same or different: (C1-6) alkyl, (C3-6) cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine , ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide and steroids, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic;

Z is:

I1, I2, I3, I4, I5, I6, I7 and I8 are each independently selected from the group consisting of H, halogen, (C1-6) alkyl, cycloalkyl (C3-6), alkenyl (C2-6) , cycloalkenyl (C4-6), alkynyl (C2-6), CR81R82OR83, COR84, COOR85 or CONR86R87; wherein each of said alkyl and cycloalkyl is optionally substituted with one to three cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C 1-6) alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium , nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid , squaric acid, squaric acid, oxime, hydrazine, peroxide, the same or different, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl;

R81, R82, R83, R84, R85, R86 and R87 are each independently selected from the group consisting of H, (C1-6) alkyl, cycloalkyl (C3-6), alkenyl (C2-6), cycloalkenyl (C4 -6), (C2-6) alkynyl;

L is a chain containing 1-20 groups selected from the group consisting of C (B1) (B2), O, NR3, S, S (O), S (O2), C (O) O, C (O ) NA1, OC (O) NA1, NA1C (O) NA1 and Group D, provided that O, S (O), S (O2) and C (O) O do not join directly with each other;

B1 and B2 are independently selected from the group consisting of hydrogen, (C1-6) alkyl, cycloalkyl (C3-7), aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, aryloxy, thioalkoxy (C1-6) ), cyano, halogen, nitro, C (O) R57, benzyl, -NR42C (O) -alkyl (C1-6), -NR42C (O) -cycloalkyl (C3-6), -NR42C (O) -aryl, -NR42C (O) -heteroaryl, NR42C (O) -heteroalicyclic, a cyclic N-lactam of 4, 5 or 6 members, -NR42S (O) 2-alkyl (C1-6), -NR42S (O) 2-cycloalkyl (C3 -6), -NR42S (O) 2-aryl, -NR42S (O) 2-heteroaryl, -NR42S (O) 2-heteroalicyclic, S (O) 2-alkyl (C1-6), S (O) 2-aryl, -S (O) 2 NR42R43, NR42R42, (C1-6) alkyl -C (O) NR42R43, C (O) NR42R43, NHC (O) NR42R43, OC (O) NR42R43, NHC (O) OR54, alkyl (C1 -6) -NR42R43, COOR54 and (C1-6) alkyl -COOR54; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, (C1-6) alkoxy and aryloxy optionally are substituted with one to nine equal or different halogens or one to five substituents same or different selected from group G; in which aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;

Ar1 and Ar2 are selected from the group consisting of phenyl and heteroaryl; wherein said phenyl and heteroaryl are, independently, optionally substituted with one to three same or different halogens or one to three same or different substituents selected from Group C; heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo [4,5-b] pyridinin -yl, 1H-imidazo [4,5c] pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl;

Group C is selected from the group consisting of OH, OR8, NA1A2, CN, COOR8, CONA1A2, SO2R8, SO2NA1A2, alkyl (C1-C4), cycloalkyl (C3-C6) and group D; and wherein said alkyl or cycloalkyl group is optionally substituted with one to three substitutions selected from the group of F, OH, OR8, NA1A2, COOR8, CONA1A2, SO2R8, SO2NA1A2; Y

Group D is selected from the group consisting of phenyl and heteroaryl; wherein said phenyl and heteroaryl are, independently, optionally substituted with one to three same or different halogens or from one to

three identical or different substituents selected from Group C; heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo [4,5-b] pyridinin -yl, 1H-imidazo [4,5c] pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl which is different from

Another embodiment of the present invention relates to a compound of Formula I above for use in the treatment of mammals infected with a virus, especially in which the virus is HIV, which comprises administering to said mammal an effective antiviral amount of a compound of the above Formula I and one or more pharmaceutically acceptable carriers, excipients and / or diluents. Optionally, the compound of Formula I may be administered in combination with an effective antiviral amount of an AIDS treatment agent selected from the group consisting of: (a) an antiviral agent against AIDS; (b) an anti-infective agent; (c) an immunomodulator; and (d) other inhibitors of HIV entry.

Another embodiment of the present invention is directed to a pharmaceutical composition comprising an effective antiviral amount of a compound of formula I and one or more pharmaceutically acceptable carriers, excipients, diluents and optionally in combination with an effective antiviral amount of a treatment agent of the AIDS selected from the group consisting of: (a) an antiviral agent against AIDS; (b) an anti-infective agent; (c) an immunomodulator; and (d) other inhibitors of HIV entry.

In another embodiment of the invention, one or more processes are provided for the manufacture of the compounds of Formula I.

The present invention relates to these, as well as other important purposes, which are described hereinafter.

Detailed description of the achievements

Since the compounds set forth herein may possess asymmetric centers and, therefore, be produced as mixtures of diastereomers and enantiomers, the present invention includes the individual diastereoisomeric and enantiomeric forms of the compounds of Formula I in addition to the mixtures thereof.

Definitions

Unless specifically stated otherwise elsewhere in the application, one or more of the following terms may be used in this document and shall have the following meanings:

The term "H" refers to hydrogen, including its isotopes. The term "C1-6 alkyl" as used herein and in the claims (unless it is specify otherwise) means straight or branched chain alkyl groups, such as methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and the like.

"C1-C4 fluoroalkyl" refers to C1-C4 alkyl substituted with F in which at least one H atom is substituted with an F atom and each H atom can be independently substituted with an F atom.

"Halogen" refers to chlorine, bromine, iodine or fluorine.

An "aryl" or "Ar" group refers to entirely monocyclic or polycyclic carbon groups of fused rings (ie, rings that share adjacent pairs of carbon atoms) that have a fully conjugated pi electron system. Examples, without limitation, of aryl groups are: phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted, the substituted group or groups are preferably one or more selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,

alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfinyl sulfonyl, sulfonamido, trihalomethyl, ureido, amino and -NRxRy, in which Rx and Ry are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, C-carboxy, sulfonyl, trihalomethyl and, combined, a five or six member heteroalicyclic ring.

As used herein, a "heteroaryl" group refers to a monocyclic or fused ring group (ie, rings that share an adjacent pair of atoms) having one or more atoms selected from the ring or rings group consisting of nitrogen, oxygen and sulfur and, in addition, that has a fully conjugated pi electron system. Unless otherwise indicated, the heteroaryl group may be attached to either a carbon or nitrogen atom within the heteroaryl group. It should be noted that the term "heteroaryl" is intended to encompass a parental heteroaryl N-oxide if such an N-oxide is chemically feasible as is known in the art. Examples, without limitation, of heteroaryl furyl, thienyl, benzothienyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyrolinyl, pyrolinyl, pyrolinyl , purinyl, carbazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, pyrazinyl, diazinyl, pyrazine, triazinyl, tetrazinyl and tetrazolyl. When substituted, the substituted group or groups are preferably one or more selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thioalkoxy, thiohydroxy, thioaryloxy, thioheteroaryloxy, thioheteroalkoxy, cyano nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, amino and -NRxRy, in which Rx and Ry are as it is They have defined above.

As used herein, a "heteroalicyclic" group refers to a monocyclic or fused ring group having one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur in the ring or rings. The rings are selected from those that provide stable link arrangements and are not intended to encompass systems that would not exist. The rings can also have one or more double bonds. However, the rings do not have a fully conjugated pi electron system. Examples, without limitation, of azetidinyl, piperidyl, piperazinyl, imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl, thiomorpholinyl and tetrahydropyranyl heteroalicyclic groups. When substituted, the substituted group or groups are preferably one or more selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thioheteroaryloxy, thioheteroalkoxy, cyano nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, Namido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido, trihalomethanesulfon, trihalomethanes silyl, guanyl, guanidino, ureido, phosphonyl, amino and -NRxRy, in which Rx and Ry are as defined above.

An "alkyl" group refers to a saturated aliphatic hydrocarbon that includes straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms (provided that a numerical range is indicated herein, for example, "1 to 20", means that the group, in this case the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, it is a medium-sized alkyl having 1 to 10 carbon atoms. Much more preferably, it is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. When substituted, the substituent group is preferably one or more individually selected from trihaloalkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halo , nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, Namido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido, trihalomethanes and combined, a five or six membered heteroalicyclic ring.

A "cycloalkyl" group refers to a group entirely of monocyclic carbon or fused rings (ie, rings that share and adjacent carbon pair) in which one or more rings do not have a fully conjugated pi electron system. Examples are, without limitation, cycloalkyl cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene and adamantane groups. A cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent group or groups are preferably one or more individually selected from alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thioheteroaryloxy, thioheteroalicyclo, cyano, halo, nitro , carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, Nthiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido, trihalomethanesulfon, trihalomethanesulfon , guanyl, guanidino, ureido, phosphonyl, amino and -NRxRy with Rx and Ry as defined above.

An "alkenyl" group refers to an alkyl group, as defined herein, which has at least two carbon atoms and at least one carbon-carbon double bond.

An "alkynyl" group refers to an alkyl group, as defined herein, which has at least two carbon atoms and at least one carbon-carbon triple bond.

A "hydroxy" group refers to a -OH group.

An "alkoxy" group refers to both an -O-alkyl group and a -O-cycloalkyl group as defined in the

present document An "aryloxy" group refers to both an -O-aryl group and an -O-heteroaryl group, as defined in the present document

A "heteroaryloxy" group refers to a heteroaryl-O-with heteroaryl group as defined herein.

document. A "heteroalicycloxy" group refers to a heteroalicyclic-O-con heteroalicyclic group as defined herein. document.

A "thiohydroxy" group refers to a -SH group.

A "thioalkoxy" group refers to both an S-alkyl and a -S-cycloalkyl group, as defined herein. document. A "thioaryloxy" group refers to both an -S-aryl group and an -S-heteroaryl group, as defined in the

present document

A "thioheteroaryloxy" group refers to a heteroaryl-S-with heteroaryl group as defined herein. document. A "thioheteroalicycloxy" group refers to a heteroalicyclic-S-group with heteroalicyclic as defined in the

present document A "carbonyl" group refers to a group -C (= O) -R "in which R" is selected from the group consisting of

hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and heteroalicyclic (attached through a ring carbon), as each is defined herein. An "aldehyde" group refers to a carbonyl group in which R "is hydrogen. A "thiocarbonyl" group refers to a group -C (= S) -R "with R" as defined herein. A "keto" group refers to a -CC (= O) C-group in which the carbon on one or both sides of the C = O can be

alkyl, cycloalkyl, aryl or a carbon of a heteroaryl or heteroalicyclic group. A "trihalomethanecarbonyl" group refers to a Z3CC (= O) group - said Z being a halogen. A "C-carboxy" group refers to a group -C (= O) OR ", with R" as defined herein. An "O-carboxy" group refers to a group R "C (-O) O-, with R" as defined herein. A "carboxylic acid" group refers to a C-carboxy group in which R "is hydrogen. A "trihalomethyl" group refers to a -CZ3 group, in which Z is a halogen group as defined herein.

document. A "trihalomethanesulfonyl" group refers to a Z3CS (= O) 2-with Z group as defined above. A "trihalomethanesulfonamido" group refers to a Z3CS (= O) 2NRx-con Z group as defined above.

and Rx H or (C1-6) alkyl. A "sulfinyl" group refers to a group -S (= O) -R ", where R" is C1-6 alkyl. A "sulfonyl" group refers to a group -S (= O) 2R "where R" is (C1-6) alkyl An "S-sulfonamido" group refers to a -S (= O) 2NRXRY, RX and RY being independently H or (C1-6) alkyl. An "N-Sulfonamido" group refers to an R "S (= O) 2NRX- group, where Rx H or (C1-6) alkyl. An "O-carbamyl" group refers to a -OC (= O) NRxRy group, Rx and Ry being independently H or (C1-6) alkyl. An "N-carbamyl" group refers to an RxOC (= O) NRy group, Rx and Ry being independently H or (C1-6) alkyl. An "O-thiocarbamyl" group refers to a -OC (= S) NRxRy group, where Rx and Ry independently H or (C1 alkyl)

6). An "N-thiocarbamyl" group refers to an RxOC (= S) NRy- group, Rx and Ry being independently H or (C16) alkyl.

An "amino" group refers to a group -NH2. A "C-amido" group refers to a group -C (= O) NRxRy, Rx and Ry being independently H or (C1-6) alkyl. A "C-thioamido" group refers to a -C (= S) NRxRy group, Rx and Ry being independently H or (C1-6) alkyl. An "N-amido" group refers to an RxC (= O) NRy- group, Rx and Ry being independently H or (C1-6) alkyl. A "ureido" group refers to a group -NRxC (= O) NRyRy2, where Rx, Ry and Ry2 are independently H or (C1-6) alkyl. A "guanidino" group refers to a group -RxNC (= N) NRyRy2, where Rx, Ry and Ry2 are independently H or alkyl

(C1-6). A "guanyl" group refers to an RxRyNC (= N) - group, where Rx and Ry are independently H or (C1-6) alkyl. A "cyano" group refers to a -CN group. A "silyl" group refers to a -Si (R ") 3, where R" (C1-6) alkyl or phenyl. A "phosphonyl" group refers to a P (= O) (ORx) 2 where Rx is (C1-6) alkyl. A "hydrazino" group refers to a group -NRxNRyRy2, where Rx, Ry and Ry2 are independently H or (C1-6) alkyl. A group "4, 5 or 6-membered ring cyclic N-lactam" refers to

Any two adjacent R groups can be combined to form an additional aryl, cycloalkyl, heteroaryl or heterocyclic ring fused to the ring initially bearing those R groups.

It is known in the art that nitrogen atoms in heteroaryl systems can "participate in a double heteroaryl ring bond" and this refers to the form of double bonds in the two tautomeric structures comprising the five-membered ring heteroaryl groups. This dictates whether nitrogen can be substituted as is well known by chemists in the art. The disclosure and claims of the present invention are based on the general known principles of the chemical bond. It is understood that the claims do not encompass structures known to be unstable or not capable of existing based on the literature.

Pharmaceutically acceptable salts of the compounds disclosed herein are within the scope of the invention. The term "pharmaceutically acceptable salt" as used herein and in the claims is intended to include non-toxic base addition salts. Suitable salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid and the like. The term "pharmaceutically acceptable salt" as used herein is also intended to include salts of acidic groups, such as a carboxylate, with counterions such as ammonium, alkali metal salts, especially sodium or potassium salts, alkaline earth metal salts, in particular calcium or magnesium and salts with suitable organic bases such as lower alkylamines (methylamine, ethylamine, cyclohexylamine and the like) or with substituted lower alkylamines (for example, hydroxy substituted alkylamines such as diethanolamine, triethanolamine or tris (hydroxymethyl) aminomethane) or with bases such as piperidine or morpholine.

As set forth above, the invention relates to compounds of Formula I, including pharmaceutically acceptable salts thereof:

in which A is selected from the group consisting of:

in which

5 a, b, c, d and e are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, COOR56, XR57, NA1A2, C (O) R7, C (O) NR55R56, B, Q and E;

B is selected from the group consisting of -C (= NR46) (R47), C (O) NR40R41, aryl, heteroaryl, heteroalicyclic, S (O) 2R8, S (O) 2NR40R41, C (O) R7, XR8a, (C1-6) alkyl -NR40R41, (C1-6) alkyl -COOR8b; in which said aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or of 10 one to three identical or different substituents selected from the group F; in which aryl is naphthyl or phenyl replaced; wherein heteroaryl is a mono or bicyclic system that contains 3 to 7 ring atoms for a monocyclic system and up to 12 atoms in a condensed bicyclic system, including 1 to 4 heteroatoms; wherein the heteroalicyclic is a 3- to 7-membered cyclic mono ring that may contain 1 to 2 heteroatoms in the main chain of the ring and which may be condensed with a benzene or pyridine ring;

Q is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl and (C2-6) alkenyl; wherein said (C1-6) alkyl and (C2-6) alkenyl are optionally substituted with one to three same or different halogens or one to three same or different substituents selected from the group consisting of C (O) NR55R56, hydroxy, cyano and XR57;

E is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl and (C2-6) alkenyl; in which said

(C1-6) alkyl and (C2-6) alkenyl are, independently, optionally substituted with a member selected from the group consisting of phenyl, heteroaryl, SMe, SPh, -C (O) NR56R57, C (O) R57 , SO2-C1-6 alkyl and SO2Ph; wherein heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms;

F is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic,

Hydroxy, (C1-6) alkoxy, aryloxy, thioalkoxy (C1-6), cyano, halogen, nitro, -C (O) R57, benzyl, -NR42C (O) -alkyl (C1-6), NR42C (O ) -C3-6 cycloalkyl, -NR42C (O) -aryl, -NR42C (O) -heteroaryl, -NR42C (O) -heteroalicyclic, a 4, 5 or 6-membered cyclic ring N-lactam, -NR42S (O) 2-C 1-6 alkyl, -NR42S (O) 2-cycloalkyl (C3-6), -NR42S (O) 2-aryl, NR42S (O) 2-heteroaryl, -NR42S (O) 2- heteroalicyclic, S (O) 2-(C1-6) alkyl, S (O) 2aryl, -S (O) 2 NR42R43, NR42R43, (C1-6) alkyl -C (O) NR42R43, C (O) NR42R43, NHC (O) NR42R43, OC (O) NR42R43, NHC (O) OR54, (C1-6) alkyl -NR42R43,

COOR54 and (C1-6) alkyl -COOR54; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, (C1-6) alkoxy and aryloxy optionally are substituted with one to nine equal or different halogens or one to five substituents same or different selected from group G; in which aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; Heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,

Tetrahydrofuran, tetrahydropyran, azepine and morpholine;

G is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, aryloxy, cyano, halogen, nitro, -C (O ) R57, benzyl, -NR48C (O) -alkyl (C1-6), -NR48C (O) cycloalkyl (C3-6), -NR48C (O) -aryl, -NR48C (O) -heteroaryl, -NR48C (O ) -heteroalicyclic, a 4, 5 or 6-membered ring cyclic N-lactam, -NR48S (O) 2-C 1-6 alkyl, -NR48S (O) 2-cycloalkyl (C3-6), -NR48S ( O) 2-aryl,

NR48S (O) 2-heteroaryl, -NR48S (O) 2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR48R49, alkyl (C1-6) C (O) NR48R49, C (O) NR48R49, NHC (O) NR48R49, OC (O) NR48R49, NHC (O) OR54 ', (C1-6) alkyl -NR48R49, COOR54 and (C1-6) alkyl -COOR54; in which aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;

R7 is selected from the group consisting of (C1-6) alkyl, (C2-6) alkenyl, (C3-7) cycloalkyl, aryl, heteroaryl and heteroalicyclic; wherein said aryl, heteroaryl and heteroalicyclic are optionally substituted with one to

three same or different halogens or with one to three same or different substituents selected from the group F;

wherein for R7, R8, R8a, R8b aryl is phenyl; heteroaryl is a mono or bicyclic system that contains 3 to 7 ring atoms for monocyclic systems and up to 10 atoms in a bicyclic system, including 1 to 4 heteroatoms; wherein heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;

R8 is selected from the group consisting of hydrogen, (C1-6) alkyl, cycloalkyl (C3-7), alkenyl (C2-6), cycloalkenyl (C3-7), alkynyl (C2-6), aryl, heteroaryl and heteroalicyclic; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, (C2-6) alkenyl, (C3-7) cycloalkenyl, (C2-6) alkynyl, aryl, heteroaryl and heteroalicyclic optionally is substituted with one to six equal or different halogens or one to five identical or different substituents selected from the group F or (C1-6) alkyl, cycloalkyl (C3-6), cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-) alkoxy 6), halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate , sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl;

R8a is a member selected from the group consisting of aryl, heteroaryl and heteroalicyclic; wherein each member is optionally independently substituted with one to six same or different halogens

or from one to five identical or different substituents selected from the group F;

R8b is selected from the group consisting of hydrogen, (C1-6) alkyl and phenyl;

X is selected from the group consisting of NH or NCH3, O and S;

R40 and R41 are independently selected from the group consisting of (a) hydrogen; (b) (C1-6) alkyl or (C3-7) cycloalkyl substituted with one to three same or different halogens or one to two same or different substituents selected from the group F or different functional groups: (C1-6) alkyl , C3-6 cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, C1-6 alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfonamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine , peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl; and (c) (C1-6) alkoxy, aryl, heteroaryl or heteroalicyclic; or R40 and R41 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine and morpholine; and wherein said aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or one to two same or different substituents selected from the group F; in which for R40 and R41 aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 6 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; provided that when B is C (O) NR40R41, at least one of R40 and R41 is not selected from groups (a) or (b);

R42 and R43 are independently selected from the group consisting of hydrogen, (C1-6) alkyl, allyl, (C1-6) alkoxy, (C3-7) cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R42 and R43 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine and morpholine; and wherein said (C1-6) alkyl, (C1-6) alkoxy, (C3-7) cycloalkyl, aryl, heteroaryl and heteroalicyclic acid are optionally substituted with one to three same or different halogens or one to two equal substituents or different selected from group G or different functional groups: (C1-6) alkyl, (C3-6) cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, halogen, benzyl, primary amine , secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl; in which for R42 and R43 aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 6 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;

R46 is selected from the group consisting of H, phenyl, aryl, heteroaryl and (C1-6) alkyl, OR57 and NR55R56;

R47 is selected from the group consisting of H, amino, hydroxyl, phenyl, aryl, heteroaryl and (C1-6) alkyl;

R48 and R49 are independently selected from the group consisting of hydrogen, (C1-6) alkyl, phenyl, aryl and heteroaryl;

R50 is selected from the group consisting of H, (C1-6) alkyl, (C3-6) cycloalkyl and benzyl; wherein each of said (C1-6) alkyl, (C3-7) cycloalkyl and benzyl are optionally substituted with one to three (C1-6) alkyl, (C3-6) cycloalkyl, cyano, phenyl, aryl, heteroaryl , heteroalicyclic, hydroxy, (C1-6) alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone , sulfonamide, sulfonamide, acyl sulfonamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squared acid, squaric acid, oxime, hydrazine, peroxide, equal or different, among which ether, peroxide, thioether , secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl

R54 is selected from the group consisting of hydrogen and (C1-6) alkyl;

R54 'is (C1-6) alkyl;

R55 and R56 are independently selected from the group consisting of hydrogen and (C1-6) alkyl;

and R57 is selected from the group consisting of hydrogen, (C1-6) alkyl, aryl, heteroaryl; Y

A1 and A2 are independently selected from hydrogen, (C1-6) alkyl, aryl, heteroaryl, SO2D1, SO2ND2D3, COD4, COCOD4, COOD4, COND5D6, COCOND5D6, COCOOD4, C (= ND7) D8, C (= ND9) ND10D11;

A1 and A2 can either connect to each other or join to form a ring structure;

D1, D2, D3, D4, D5, D6, D7, D8, D9, D10 and D11 are each independently selected from the group consisting of H, C1-C50 alkyl, C3-C50 cycloalkyl, C3-C50 alkenyl, cycloalkenyl C4-C50, phenyl, heteroaryl, C3-C50 amide and C3-C50 ether; heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo [4,5-b] pyridinin -yl, 1H-imidazo [4,5-c] pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl; provided that the carbon atoms comprising the carbon-carbon double bond of said C3-C20 alkenyl or the carbon-carbon triple bond of said C3-C20 alkynyl are not the point of attachment with the nitrogen to which D2 binds, D3, D5, D6, D7, D9, D10 and D11; wherein said C1-C50 alkyl, C3-C50 cycloalkyl, C3-C50 alkenyl, C4-C50 cycloalkenyl, aryl, phenyl, heteroaryl, C3-C50 amide and C3-C50 ether are optionally substituted with one to three of the following functionalities , same or different: (C1-6) alkyl, (C3-6) cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine , ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide and steroids, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic;

Z is:

I1, I2, I3, I4, I5, I6, I7 and I8 are each independently selected from the group consisting of H, halogen, (C1-6) alkyl, cycloalkyl (C3-6), alkenyl (C2-6) , cycloalkenyl (C4-6), alkynyl (C2-6), CR81R82OR83, COR84, COOR85 or CONR86R87; wherein each of said alkyl and cycloalkyl is optionally substituted with one to three cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C 1-6) alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium , nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid , squaric acid, squaric acid, oxime, hydrazine, peroxide, the same or different, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,

pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl;

R81, R82, R83, R84, R85, R86 and R87 are each independently selected from the group consisting of H, (C1-6) alkyl, cycloalkyl (C3-6), alkenyl (C2-6), cycloalkenyl (C4 -6), (C2-6) alkynyl;

L is a chain containing 1-20 groups selected from the group consisting of C (B1) (B2), O, NR3, S, S (O), S (O2), C (O) O, C (O ) NA1, OC (O) NA1, NA1C (O) NA1 and Group D, provided that O, S (O), S (O2) and C (O) O do not join directly with each other;

B1 and B2 are independently selected from the group consisting of hydrogen, (C1-6) alkyl, cycloalkyl (C3-7), aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, aryloxy, thioalkoxy (C1-6) ), cyano, halogen, nitro, C (O) R57, benzyl, -NR42C (O) -alkyl (C1-6), -NR42C (O) -cycloalkyl (C3-6), -NR42C (O) -aryl, -NR42C (O) -heteroaryl, NR42C (O) -heteroalicyclic, a cyclic N-lactam of 4, 5 or 6 members, -NR42S (O) 2-alkyl (C1-6), -NR42S (O) 2-cycloalkyl (C3 -6), -NR42S (O) 2-aryl, -NR42S (O) 2-heteroaryl, -NR42S (O) 2-heteroalicyclic, S (O) 2-alkyl (C1-6), S (O) 2-aryl, -S (O) 2 NR42R43, NR42R42, (C1-6) alkyl -C (O) NR42R43, C (O) NR42R43, NHC (O) NR42R43, OC (O) NR42R43, NHC (O) OR54, alkyl (C1 -6) -NR42R43, COOR54 and (C1-6) alkyl -COOR54; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, (C1-6) alkoxy and aryloxy optionally are substituted with one to nine equal or different halogens or one to five substituents same or different selected from group G; in which aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;

Ar1 and Ar2 are selected from the group consisting of phenyl and heteroaryl; wherein said phenyl and heteroaryl are, independently, optionally substituted with one to three same or different halogens or one to three same or different substituents selected from Group C; heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo [4,5-b] pyridinin -yl, 1H-imidazo [4,5c] pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl;

Group C is selected from the group consisting of OH, OR8, NA1A2, CN, COOR8, CONA1A2, SO2R8, SO2NA1A2, alkyl (C1-C4), cycloalkyl (C3-C6) and group D; and wherein said alkyl or cycloalkyl group is optionally substituted with one to three substitutions selected from the group of F, OH, OR8, NA1A2, COOR8, CONA1A2, SO2R8, SO2NA1A2; Y

Group D is selected from the group consisting of phenyl and heteroaryl; wherein said phenyl and heteroaryl are, independently, optionally substituted with one to three same or different halogens or one to three same or different substituents selected from Group C; heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo [4,5-b] pyridinin -yl, 1H-imidazo [4,5c] pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl which is different from

The most preferred compounds of Formula I include those selected from the group of:

Y

including pharmaceutically acceptable salts thereof. Of the above,

even more preferred, including pharmaceutically acceptable salts thereof.

The compounds of the present invention, in accordance with all the various embodiments described above, can be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray or by rectally, and by other means, in unit dosage forms containing non-toxic pharmaceutically acceptable carriers, excipients and diluents available to the person skilled in the art. One or more adjuvants may also be included.

Therefore, in accordance with the present invention, a pharmaceutical composition for the treatment of viral infections such as HIV infection and AIDS is additionally provided. The treatment involves the administration to a patient in need of said treatment of a pharmaceutical composition containing an effective antiviral amount of one or more compounds of Formula I, together with one or more pharmaceutically acceptable carriers, excipients and / or diluents. As used herein, the expression "antiviral amount

"Effective" means the total amount of each active component of the composition and the use that is sufficient to show a significant benefit to the patient, that is, the inhibition, improvement or cure of acute conditions, characterized by the inhibition of HIV infection: When applied to an individual active ingredient, administered alone, the expression refers to that ingredient only.When applied to a combination, the expression refers to combined amounts of the active ingredients that result in the therapeutic effect , either

20 administered in combination, in series or simultaneously. The terms "treat, treat, treatment" as used herein and in the claims mean preventing, improving or curing diseases associated with HIV infection.

The pharmaceutical compositions of the invention may be in the form of orally administrable suspensions or tablets; as well as nasal sprays, sterile injectable preparations, for example, in the form of

sterile injectable aqueous or oleaginous suspensions or suppositories. Pharmaceutically acceptable carriers, excipients and / or diluents can be used in the pharmaceutical compositions and are those used in the art of pharmaceutical preparations.

When administered orally in the form of a suspension, these compositions are prepared according to techniques normally known in the art of the pharmaceutical formulation and may contain microcrystalline cellulose to transmit volume, alginic acid or sodium alginate as suspending agent, methylcellulose as a viscosity enhancer and sweeteners / flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and / or other excipients, binders, expanders, disintegrants, diluents and lubricants known in the art.

Injectable solutions or suspensions may be formulated according to the known technique, using suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution or dispersing agents or humectants and suspensions, such as nonvolatile, sterile, mild oils, including mono- or synthetic diglycerides and fatty acids, including oleic acid.

The compounds herein can be administered orally to humans in a dosage range of 1 to 100 mg / kg of body weight in divided doses, usually over a prolonged period, such as days, weeks, months or even years. . A preferred dosage range is 1 to 10 mg / kg body weight orally in divided doses. Another preferred dosage range is 1 to 20 mg / kg body weight in divided doses. It will be understood, however, that the specific dose level and dosage frequency for any particular patient can be varied and will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and the duration of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, combination of drugs, the severity of the particular condition and the host undergoing therapy.

Also contemplated herein are combinations of the compounds of Formula I set forth herein, together with one or more agents useful in the treatment of AIDS. For example, the compounds set forth herein can be effectively administered, either in pre-exposure and / or post-exposure periods, in combination with effective amounts of AIDS antivirals, immunomodulators, anti-infectives or vaccines, such as those in the following non-limiting table:

ANTIVIRALS

Drug name

Maker Indication

Rilpivirine

Tibotec HIV infection, AIDS, CRS (inhibitor no

reverse transcriptase nucleoside)

Complete ®

Gilead HIV infection, AIDS, CRS; combination with

emtricitabine, rilpivirine and disoproxil fumarate of

tenofovir

097

Hoechst / Bayer HIV infection, AIDS, CRS (inhibitor no

nucleoside reverse transcriptase (TI))

Amprenavir

Glaxo Wellcome HIV infection, AIDS, CRS (inhibitor of

141 W94

protease)

GW 141

Abacavir (1592U89)

Glaxo Wellcome HIV infection, AIDS, CRS (IT inhibitor)

GW 1592

Acemannan

Carrington Labs CRS

(Irving, TX)

Acyclovir

Burroughs HIV infection, AIDS, CRS

Wellcome

AD-439

Tanox Biosystems HIV infection, AIDS, CRS

AD-519

Tanox Biosystems HIV infection, AIDS, CRS

Adefovir Dipivoxil

Gilead Sciences HIV infection

AL-721

Ethigen (LosÁngeles, CA) CRS, LGP HIV positive, AIDS

Interferon Alfa

Glaxo Wellcome Kaposi's sarcoma, HIV in combination with

Move back

Ansamycin

Adria Laboratories CRS

LM 427

(Dublin, OH)

Erbamont

(Stamford, CT)

Drug name

Antibody that neutralizes pH labile aberrant alpha interferon

AR177 Beta-fluoro-ddA

BMS-234475 (CGP-61755), the

CI-1012 Cidofovir sulfate from curdlan

(continued) Manufacturer

Advanced Biotherapy Concepts (Rockville, MD) Aronex Pharm National Cancer Institute Bristol-Myers Squibb / Novartis Warner-Lambert Gilead Science AJIPharma USA

Medlmmune cytomegalovirus immunoglobin

Cytovene Ganciclovir Darunavir

Delaviridine

Dextran sulfate

ddC dideoxycytidine ddI dideoxyinosine

DMP-450

Efavirenz (DMP 266, Sustiva®) (-) - chloro-4- (S) -cyclopropylenyl-4 (S) trifluoro-methyl-1,4-dihydro-2H-3,1benzoxazin-2-one, STOCRINE EL10

Etravirine

Famciclovir GS 840

HBY097

Hyperferin Interferon beta recombinant human Interferon alfa-n3 Indinavir

ISIS 2922 KNI-272 Lamivudine, 3TC Lobucavir Nelfinavir Nevirapine Novapren Syntex

Tibotec-J & J

Pharmacia-Upjohn

Ueno Fine Chem. Ind. Ltd. (Osaka, Japan) Hoffman-La Roche Bristol-Myers Squibb AVID (Camden, NJ)

Bristol Myers Squibb

Elan Corp, PLC (Gainesville, GA) Tibotec / J&J

Smith Kline Gilead

Hoechst Marion Roussel VIMRx Pharm. Triton Biosciences (Almeda, CA) Interferon Sciences Merck

ISIS Pharmaceuticals National Cancer Institute Glaxo Wellcome

Bristol-Myers Squibb Agouron Pharmaceuticals Boeheringer Ingleheim Novaferon Labs, Inc. (Akron, OH)

Indication

AIDS, CRS

HIV infection, AIDS, CRS diseases associated with AIDS

HIV infection, AIDS, CRS (protease inhibitor) HIV-1 infection CMV retinitis, herpes, papillomavirus HIV infection CMV retinitis Sight threatened by CMV, peripheral CMV retinitis HIV infection, AIDS, CRS (inhibitor of protease) HIV infection, AIDS, CRS (RT inhibitor) AIDS, CRS, asymptomatic HIV positive

HIV infection, AIDS, CRS HIV infection, AIDS, CRS; combination with AZT / d4T HIV infection, AIDS, CRS (protease inhibitor) HIV infection, AIDS, CRS (non-nucleoside IT inhibitor)

HIV infection

HIV infection, AIDS, CRS (non-nucleoside reverse transcriptase inhibitor) Herpes zoster, herpes simplex HIV infection, AIDS, CRS (reverse transcriptase inhibitor) HIV infection, AIDS, CRS (non-nucleoside reverse transcriptase inhibitor ) HIV infection, AIDS, CRS AIDS, Kaposi sarcoma, CRS

CRS, AIDS HIV infection, AIDS, CRS, asymptomatic HIV positive, also in combination with AZT / ddI / ddC CMV retinitis

HIV associated diseases

HIV infection, AIDS, CRS (reverse transcriptase inhibitor); also with AZT CMV infection

HIV infection, AIDS, CRS (protease inhibitor) HIV infection, AIDS, CRS (IT inhibitor) HIV inhibitor

Indication

AIDS

CMV retinitis, HIV infection, other CMV infections HIV infection, AIDS, CRS (protease inhibitor) HIV infection, AIDS HIV infection, AIDS, CRS

HIV infection, AIDS, CRS (protease inhibitor) HIV infection, AIDS, CRS (protease inhibitor) HIV infection, AIDS, CRS

HIV infection, AIDS, CRS (protease inhibitor) genital HSV and asymptomatic HIV positive CMV infections, ALS, CRS

HIV infection, AIDS, CRS HIV infection, AIDS, CRS, with AZT

HIV infection, AIDS, CRS, Kaposi's sarcoma, in combination with other therapies HIV infection, AIDS, (reverse transcriptase inhibitor) HIV infection, AIDS, (reverse transcriptase inhibitor) HIV infection, AIDS, ( reverse transcriptase inhibitor) HIV infection, AIDS, (reverse transcriptase inhibitor) HIV infection, AIDS, protease inhibitor

HIV infection, AIDS, viral fusion inhibitor HIV infection, AIDS, viral protease inhibitor HIV infection, AIDS, (developing CCR5 antagonist) HIV infection, AIDS, (combination of three drugs) HIV, AIDS, (CCR5 antagonist, developing) HIV infection, AIDS, (CCR5 antagonist, developing) HIV infection, AIDS, (CCR5 antagonist, developing) HIV infection, AIDS

Tenofovir disoproxil (Viread®) and Emtriva® (emtricitabine) fumarate salt combination HIV infection

Developing AIDS Combination of disoproxil fumarate salt of tenofovir (Viread®), Emtriva® (emtricitabine) and Sustiva® (efavirenz) HIV infection, AIDS, developing

Drug Name Octapeptide Sequence of

Peptide T Trisodium phosphonoformate PNU-140690 Probucol

RBC-CD4 Ritonavir Saquinavir Stavudine; d4T Dideshydrodeoxy

thymidine

Tipranavir Valacyclovir Virazol Ribavirin

VX-478 Zalcitabine

Zidovudine; AZT Tenofovir disoproxil, salt of fumarate (Viread) Emtriva® (emtricitabine) (FTC)

Combivir®

Abacavir succinate (or Ziagen®) GSK

Reyataz® (or atazanavir) Bristol-Myers

Squibb Fuzeon® (enfuvirtide or T-20) Roche / Trimeris Lexiva® (or calcium fosamprenavir) GSK / Vertex

Selzentry Maraviroc; (Pfizer document

(continued) Manufacturer

Peninsula Labs (Belmont, CA) Astra Pharm. Products, Inc. Pharmacia Upjohn

Vyrex Sheffield Med. Tech (Houston, TX) Abbott

Hoffmann LaRoche Bristol-Myers Squibb Boehringer Ingelheim Glaxo Wellcome Viratek / ICN (Coast Mesa, CA) Vertex Hoffmann– LaRoche Glaxo Wellcome

Gilead

Gilead

GSK

UK 427857) Trizivir®

Sch-417690 (vicriviroc)

TAK-652

GSK 873140 (ONO-4128)

MK-0518 Raltegravir Truvada® integrase inhibitor

Integrase Inhibitor

GS917 / JTK-303 Elvitegravir Triple combination of Atripla® drugs

Festinavir® GSK Schering-Plow Takeda GSK / ONO Merck

Gilead

Gilead / Japan Tobacco

Gilead / Bristol-Myers Squibb

Oncolys BioPharma

(continuation) Drug Name Manufacturer Indication

CMX-157 Chimerix HIV infection, AIDS Tenofovir lipid conjugate nucleotide GSK1349572 GSK HIV infection, AIDS Integrase Inhibitor

IMMUNOMODULATORS

Drug Name Manufacturer Indication

AS-101 Wyeth-Ayerst AIDS Bropyrimine Pharmacia Upjohn Advanced AIDS Acemanano Carrington Labs, Inc. (Irving, AIDS, CRS

TX) CL246.738 Wyeth Lederle Labs AIDS, Kaposi sarcoma FP-21399 Fuki Immunopharm Blocks HIV fusion with CD4 lymphocytes + Interferon Gamma Genentech CRS, in combination with TNF (necrosis factor

tumor) Colony stimulating factor from Genetics Institute Sandoz AIDS granulocytes and macrophages Colony stimulating factor from Hoechst-Roussel Immunex AIDS granulocytes and macrophages Colony stimulating factor from Schering-Plow AIDS, combination with AZT granulocytes and macrophages Immunostimulatory HIV septum of the particles core of HIV IL-2 Interleukin-2 Cetus AIDS, in combination with AZT IL-2 Interleukin-2 Hoffman-LaRoche AIDS, CRS, HIV, in combination with AZT

Immunex IL-2 Interleukin-2 (aldeslukin) Chiron AIDS, increased CD4 lymphocyte count Intravenous immunoglobulin Cutter Biological (Berkeley, pediatric AIDS, in combination with AZT (human) CA) IMREG-1 IMREG (New Orleans, LA) AIDS, Kaposi's sarcoma, CRS, LGP IMREG-2 IMREG (New Orleans, LA) AIDS, Kaposi's sarcoma, CRS, LGP Diethyl ditium imutiol carbamate Merieux Institute AIDS, CRS Interferon alpha-2 Schering Plough Kaposi's sarcoma with AZT, AIDS Methionine -encephalin TNI Pharmaceutical (Chicago, AIDS, CRS

IL) MTP-PE Muramil-Tripeptide Ciba-Geigy Corp. Sarcoma of Kaposi Amgen AIDS colony stimulating factor, in combination with AZT granulocytes Remune Immune Response Corp. Immunotherapeutic rCD4 soluble human CD4 Genentech AIDS, CRS recombinant Hybrid rCD4-IgG AIDS, CRS Recombinant soluble human CD4 Biogen AIDS, CRS

Interferon Alfa 2a Hoffman-La Roche Sarcoma from Kaposi, AIDS, CRS, in combination

with AZT T4 Soluble SK & F106528 Smith Kline HIV infection Thimopentin Immunobiology Research HIV infection

Institute (Annandale, NJ) Tumor Necrosis Factor; TNF Genentech CRS, in combination with interferon gamma

ANTI-INFECTIVE

Drug Name Manufacturer Indication

Clindamycin with primaquine Pharmacia Upjohn NPC Fluconazole Pfizer Cryptococcal meningitis, candidiasis Nystatin Squibb Corp tablet. Prevention of oral candidiasis Ornidyl Eflornithine Merrell Dow NPC Pentamidine Isethionate (IM and IV) Lyphomed (Rosemont, IL) NPC Treatment Trimethoprim Antibacterial Trimethoprim / sulfa Antibacterial

(continuation)

ANTI-INFECTIVE

Drug name

Maker Indication

Piritrexim

Burroughs Wellcome NPC treatment

Pentamidine Isethionate for

Fisons Corporation NPC prophylaxis

inhalation

Spiramycin

Rhône-Poulenc Cryptosporidia diarrhea

Itraconazole-R51211

Janssen-Pharm. Histoplasmosis; cryptococcal meningitis

Trimetrexate

Warner-Lambert NPC

Daunorubicin

NeXstar, Sequus Kaposi's sarcoma

Human erythropoietin

Ortho Pharm.Corp. Severe anemia associated with AZT therapy

recombinant

Human growth hormone

Serono Impairment related to AIDS, cachexia

recombinant

Megestrol Acetate

Bristol-Myers Squibb Treatment of AIDS-associated anorexia

Testosterone

Rise, Smith Kline AIDS related deterioration

Total Enteral Nutrition

Norwich Eaton Diarrhea and AIDS-related malabsorption

Pharmaceuticals

Additionally, the compounds of the invention set forth herein can be used in combination with other HIV entry inhibitors. Examples of such HIV entry inhibitors are analyzed in Drugs of the Future, 24 (12): 1355-1362 (1999); Cell, 9: 243-246 (Oct. 29, 1999); and Drug Discovery Today, 5 (5): 183-194 (May 2000) and Meanwell, N. A. et al., "Inhibitors of the entry of HIV into host cells", Curr. Op. Drug Disc. Dev, 6 (4): 451-461 (2003). Specifically, the compounds can be used in combination with other binding inhibitors, fusion inhibitors and chemokine receptor antagonists directed to the co-receptor either CCR5 or CXCR4.

It will be understood that the scope of combinations of the compounds set forth herein with antivirals against AIDS, immunomodulators, anti-infectives, HIV entry inhibitors or vaccines is not limited to the list in the Table above but includes, in principle, any combination with any pharmaceutical composition useful for the treatment of AIDS.

Preferred combinations are simultaneous or alternating treatments with a compound of the present invention and an HIV protease inhibitor and / or a non-nucleoside HIV reverse transcriptase inhibitor. An optional fourth component in the combination is a nucleoside HIV reverse transcriptase inhibitor, such as AZT, 3TC, ddC or ddI. A preferred HIV protease inhibitor is REYATAZ® (active ingredient Atazanavir). Normally, a dose of 300 to 600 mg is administered once daily. This can be co-administered with a low dose of Ritonavir (50 to 500 mg). Another preferred HIV protease inhibitor is KALETRA®. Another useful inhibitor of HIV protease is Indinavir, which is the N- (2 (R) -hydroxy-1- (S) indanyl) -2 (R) -phenylmethyl-4- (S) ethanolate sulfate salt -hydroxy-5- (1- (4- (3-pyridyl-methyl) -2 (S) -N '- (t-butylcarboxamido) piperazinyl)) - pentanamide and is synthesized in accordance with US Pat. . No. 5,413,999. Indinavir is usually given at a dose of 800 mg three times a day. Other preferred protease inhibitors are nelfinavir and ritonavir. Another preferred HIV protease inhibitor is saquinavir which is administered in a dosage of 600 or 1200 mg three times a day. Preferred non-nucleoside reverse HIV transcriptase inhibitors include efavirenz. These combinations may have unexpected effects on limiting the extent and extent of HIV infection. Preferred combinations include those with the following (1) indinavir with efavirenz, and, optionally, AZT and / or 3TC and / or ddI and / or ddC; (2) indinavir and any of AZT and / or ddI and / or ddC and / or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and / or zidovudine; (4) zidovudine and lamivudine and 141 W94 and 1592U89; (5) Zidovudine and Lamivudine. (The preparation of ddC, ddI and AZT are also described in EP 0 484 071).

In such combinations, the compounds set forth herein and other active agents may be administered separately or together. In addition, the administration of an item can be previous, simultaneous

or after the administration of another agent or agents.

SYNTHESIS PROCEDURES

The present invention comprises compounds of Formula I, their pharmaceutical formulations and their use in patients suffering from or susceptible to HIV infection. The compounds of Formula I include pharmaceutically acceptable salts thereof. The compounds can be prepared by methods available in the art, as well as those described after the abbreviations and include variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be manufactured by methods known in the art using readily available materials. The variables (for example, numbered "R" substituents) used to describe the synthesis of the compounds are only intended to illustrate how to make the compounds and should not be confused with the variables used in the claims or in other sections of the specification.

Abbreviations

One or more of the following abbreviations, most of which are conventional abbreviations well known to those skilled in the art, can be used throughout the description of the invention and the examples:

h = hour or hours

ta = room temperature

mol = mol or moles

mmol = millimol or millimoles

g = gram or grams

mg = milligram or milligrams

ml = milliliter or milliliters

TFA = trifluoroacetic acid

DCE = 1,2-dichloroethane

CH2Cl2 = dichloromethane

TPAP = tetrapropylammonium perrutenate

THF = tetrahydrofuran

DEPBT = 3- (diethoxyphosphoryloxy) -1,2,3-benzotriazin-4 (3H) –ona

DMAP = 4-dimethylaminopyridine

P-EDC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide polymer supported

EDC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

DMF = N, N-dimethylformamide

Hunig base = N, N-diisopropylethylamine

MCPBA = meta-chloroperbenzoic acid

azaindole = 1H-pyrrolo-pyridine

4-azaindole = 1H-pyrrolo [3,2-b] pyridine

5-azaindole = 1H-pyrrolo [3,2-c] pyridine

6-azaindole = 1H-pyrrolo [2,3-c] pyridine

7-azaindole = 1H-pyrrolo [2,3-b] pyridine

PMB = 4-methoxybenzyl

DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

OTf = trifluoromethanesulfonoxy

NMM = 4-methylmorpholine

PIP-COPh = 1-benzoylpiperazine

NaHMDS = sodium hexamethyldisilazide

EDAC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

TMS = trimethylsilyl

DCM = dichloromethane

DCE = dichloroethane

MeOH = methanol

THF = tetrahydrofuran

EtOAc = ethyl acetate

LDA = lithium diisopropylamide

Li-TMP = 2,2,6,6-tetramethylpiperidinyl lithium

DME = dimethoxyethane

DIBALH = diisobutylaluminum hydride

HOBT = 1-hydroxybenzotriazole

CBZ = benzyloxycarbonyl

PCC = pyridinium chlorochromate

TBTU = O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate

DEBPT = 3- (diethoxyphosphoryloxy) -1,2,3-benzotriazin-4 (3H) -one

BOP = benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate

Preparation of compounds of formula I

The preparation of the mold A-CO-CO-Cl and A-CO-CO-OH has been described in detail in WO-00076521, WO-0162255, WO-0204440, WO-02062423, WO-02085301, WO-03068221 and US-2004/0063744.

Conventional conditions such as reacting amine with acyl halide 1 (Scheme 1a) and carboxylic acid 3 (Scheme 1b) can be used to prepare the desired amide products. Some general references of these methodologies and instructions for their use are contained in "Comprehensive Organic Transformation" by Richard C. Larock, Wiley-VCH, New York, 1989, 972 (carboxylic acids to amides), 979 (acid halides to amides) .

Scheme 1a represents a general procedure for the formation of an amide from a piperazine 2 derivative and an acyl chloride 1. An appropriate base (of catalytic amount to an excess amount) selected from sodium hydride, potassium carbonate , triethylamine, DBU, pyridine, DMAP or di-isopropyl ethyl amine was added to a solution of piperidine 2 derivative and acyl chloride 1 in an appropriate solvent selected from dichloromethane, chloroform, benzene, toluene, THF, diethyl ether, dioxane, acetone, N, N-dimethylformamide or pyridine at room temperature. Then, the reaction was carried out at room temperature or at an evaluated temperature of up to 150 ° C for a period of time (from 30 minutes to 48 hours) to provide the structure of Formula I. Some selected references involving such reactions include a) Indian J. Chem., Section B 1990, 29, 1077; 2) Z. Naturforsch. 1998, 53, 1216; 3) Chem. Pharm. Bull. 1992, 40, 1481; 4) Chem. Heterocycl. Compd. 2002, 38, 539.

Alternatively, as shown in Scheme 1b, a piperidine 2 derivative can be coupled with an acid 3 using conventional amide bond or peptide bond forming coupling reagents. An organic chemist skilled in the art knows many reagents for amide bond couplings and almost all of them are applicable for the realization of coupled amide products. The combination of EDAC and triethylamine in tetrahydrofuran or BOPCl and diisopropyl ethyl amine in chloroform has been used more frequently, but DEPBT or other coupling reagents such as PyBop could be used. Another useful coupling condition employs HATU ((a) J. Chem. Soc. Chem. Comm. 1994, 201; (B) J. Am. Chem. Soc. 1994, 116, 11580). Additionally, DEPBT (3- (diethoxyphosphoryloxy) -1,2,3-benzotriazin-4 (3H) -one) and N, N-diisopropylethylamine, commonly known as Hunig's base, represent another effective method of forming the amide bond and providing Compounds of Formula I. DEPBT can be purchased from Aldrich or can be prepared according to the procedure described in Organic Lett., 1999, 1, 91. Normally, an inert solvent such as DMF or THF is used, but other aprotic solvents could be used. .

Examples

The following examples illustrate typical syntheses of the compounds of Formula I as described in general above. Reagents and starting materials are readily available to a person skilled in the art.

Experimental chemistry

Typical procedures and characterization of selected examples:

Unless otherwise indicated, solvents and reagents were used directly as obtained from commercial sources and the reactions were performed under a nitrogen atmosphere. Flash chromatography was performed on silica gel 60 (particle size 0.040-0.063; EM Science supply). 1H NMR spectra were recorded on a 500 MHz Bruker DRX-500F (or Bruker DPX-300B or 300 MHz 300 Varian Gemini as indicated). Chemical shifts were presented in ppm on the δ scale with respect to δTMS = 0. The following internal references were used for residual protons in the following solvents: CDCl3 (δH 7.26), CD3OD (δH 3.30) and DMSO -d6 (δH 2.50). Conventional acronyms were used to describe multiplicity patterns: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), a (width), ap (apparent). The coupling constant (J) is in hertz. All liquid chromatography (CL) data was recorded on a Shimadzu LC-10AS liquid chromatograph using a SPD-10AV UV-Vis detector with data from

Mass spectrometry (EM) determined using a Micromass Platform for CL in electrospray mode.

HPLC procedure (i.e. compound isolation)

Purified compounds were diluted by preparative HPLC in methanol (1.2 ml) and purified using a Shimadzu LC-8A or LC-10A automated preparative HPLC system 5.

Typical procedures and characterization of selected examples: Intermediate ACOCOOH or ACOCOCI:

The preparation of the ACOCOOH or ACOCOCl intermediate was described in the previously published applications (W. Blair, et al. WO-200076521, O. Wallace, et al. WO-200204440, T. Wang, et al. Document 10 WO- 200162255 and T. Wang, et al. WO-2002062423). Some examples of ACOCOOH are listed below.

General procedure for the preparation of Formula I:

15 A)

2-Keto acid (1 eq), amine (1-5 eq), 3- (diethoxyphosphoryloxy) -1,2,3-benzotriazin-4 (3H) -one (DEPBT) or

0- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium (TBTU) tetrafluoroborate (1-5 eq) or (2-hexafluorophosphate)

(7-Aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium) (HATU) (1-5 eq) and Hunig or N-methyl morpholine base (120 100 eq) in THF or DMF The mixture was stirred at room temperature or at 115 ° C for 17 hours. THF or

DMF was removed by evaporation under reduced pressure and the residue was partitioned between ethyl acetate and solution.

saturated aqueous NaHCO3. The aqueous phase was extracted with ethyl acetate. The organic phase was combined and

dried over anhydrous MgSO4. Concentration in vacuo provided a crude product, which was purified by

titration or recrystallization or silica gel column chromatography or Shimadzu automated preparative HPLC System 25.

B)

2-Acyl chloride (1 eq.), Amine (1-5 eq.) And Hunig base or Et3N (1-100 eq.) In THF or DMF were combined. The mixture was stirred at room temperature or at 115 ° C for 17 hours. THF or DMF was removed by evaporation under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous solution of

NaHCO3. The aqueous phase was extracted with ethyl acetate. The organic phase was combined and dried over anhydrous MgSO4. Concentration in vacuo provided a crude product, which was purified by titration or recrystallization or silica gel column chromatography or Shimadzu automated preparative HPLC system.

Characterization:

Compound 1001

MS (M + H) + calc.

557

MS (M + H) + observ.

557

Holding time

2.06 min

CL conditions

Solvent A

10% MeCN -90% water -NH4OAc 5 ° mM

Solvent B

90% MeCN -10% water -NH4OAc 5 ° mM

% of initial B

0%

% of final B

100

Gradient time

2 min

Flow

4 ml / min

Wavelength

220

Pair of solvents

MeCN - Water -NH4OAc

Column

Primesphere C18-HC 4.6 x 30

Compound 1002

MS (M + H) + calc.

547.1

MS (M + H) + observ.

547.2

Holding time

1.45 min

(continuation)

CL conditions

Solvent A

90% water - 10% methanol - 0.1% TFA

Solvent B

10% water - 90% methanol - 0.1% TFA

% of initial B

0

% of final B

100

Gradient time

2 min

Flow

5 ml / min

Wavelength

220

Pair of solvents

Water - Methanol -TFA

Column

XTERRA C18 S7 3.0 x 50 ° mm

Compound 1003

MS (M + H) + calc.

447.2

MS (M + H) + observ.

447.3

Holding time

2.07 min

CL conditions

Solvent A

90% water - 10% methanol - 0.1% TFA

Solvent B

10% water - 90% methanol - 0.1% TFA

% of initial B

0

% of final B

100

Gradient time

2 min

Flow

5 ml / min

Wavelength

220

Pair of solvents

Water - Methanol -TFA

Column

XTERRA C18 S7 3.0 x 50 ° mm

Compound 1004

MS (M + H) + calc.

512.2

MS (M + H) + observ.

512.3

Holding time

2.01 min

CL conditions

Solvent A

90% water - 10% methanol - 0.1% TFA

Solvent B

10% water - 90% methanol - 0.1% TFA

% of initial B

0

% of final B

100

Gradient time

2min

Flow

5 ml / min

Wavelength

220

Pair of solvents

Water-Methanol -TFA

Column

XTERRA C18 S7 3.0 x 50 ° mm

Compound 1005

MS (M + H) + calc.

545.2

MS (M + H) + observ.

545.2

Holding time

2.08 min

(continuation)

CL conditions

Solvent A

90% water - 10% methanol - 0.1% TFA

Solvent B

10% water - 90% methanol - 0.1% TFA

% of initial B

0

% of final B

100

Gradient time

2 min

Flow

5 ml / min

Wavelength

220

Pair of solvents

Water-Methanol -TFA

Column

XTERRA MS C18 5 um 4.6 x 30 ° mm

Compound 1006

MS (M + H) + calc.

555.1

MS (M + H) + observ.

555.0

Holding time

2.13 min

CL conditions

Solvent A

90% water - 10% methanol - 0.1% TFA

Solvent B

10% water - 90% methanol - 0.1% TFA

% of initial B

0

% of final B

100

Gradient time

2 min

Flow

5 ml / min

Wavelength

220

Pair of solvents

Water-Methanol -TFA

Column

XTERRA MS C18 5 um 4.6 x 30 ° mm

Compound 1007

MS (M + H) + calc.

543.1

MS (M + H) + observ.

543.3

Holding time

2.21 min

CL conditions

Solvent A

90% water - 10% methanol - 0.1% TFA

Solvent B

10% water - 90% methanol - 0.1% TFA

% of initial B

0

% of final B

100

Gradient time

2 min

Flow

5 ml / min

Wavelength

220

Pair of solvents

Water-Methanol -TFA

Column

XTERRA C18 S7 3.0 x 50 ° mm

Compound 1008

MS (M + H) + calc.

578.1

MS (M + H) + observ.

578.2

Holding time

1.78 min

(continuation)

CL conditions

Solvent A

90% water - 10% methanol - 0.1% TFA

Solvent B

10% water - 90% methanol - 0.1% TFA

% of initial B

0

% of final B

100

Gradient time

2 min

Flow

5 ml / min

Wavelength

220

Pair of solvents

Water-Methanol -TFA

Column

XTERRA MS C18 5 um 4.6 x 30 ° mm

Compound 1009

MS (M + H) + calc.

559.2

MS (M + H) + observ.

559.2

Holding time

2.14 min

CL conditions

Solvent A

90% water - 10% methanol - 0.1% TFA

Solvent B

10% water - 90% methanol - 0.1% TFA

% of initial B

0

% of final B

100

Gradient time

2 min

Flow

5 ml / min

Wavelength

220

Pair of solvents

Water-Methanol -TFA

Column

XTERRA C18 S7 3.0 x 50 ° mm

Compound 1010

MS (M + H) + calc.

594.2

MS (M + H) + observ.

594.1

Holding time

1.71 min

CL conditions

Solvent A

90% water - 10% methanol - 0.1% TFA

Solvent B

10% water - 90% methanol - 0.1% TFA

% of initial B

0

% of final B

100

Gradient time

2 min

Flow

5 ml / min

Wavelength

220

Pair of solvents

Water-Methanol -TFA

Column

XTERRA C18 S7 3.0 x 50 ° mm

Compound 1011

MS (M + H) + calc.

590.1

MS (M + H) + observ.

590.3

Holding time

1.75 min

(continuation)

CL conditions

Solvent A

90% water - 10% methanol - 0.1% TFA

Solvent B

10% water - 90% methanol - 0.1% TFA

% of initial B

0

% of final B

100

Gradient time

2 min

Flow

5 ml / min

Wavelength

220

Pair of solvents

Water-Methanol -TFA

Column

XTERRA MS C18 5 um 4.6 x 30 ° mm

Biological data for the Examples

 "µM" means micromolar;

5  "ml" means milliliter;  "µl" means microliter;  "mg" means milligram;

The experimental materials and procedures used to obtain the results presented in Table 1 are described below.

10 cells:

 Production of the virus - The human embryonic kidney cell line, 293T (HEK 293T), was propagated in the middle of Eagle modified by Dulbecco (Invitrogen, Carlsbad, CA) containing 10% fetal bovine serum (SFB, Sigma, St. Louis, MO). MT2 cells of human T-lymphocyte leukemia (AIDS Research Program and Reference Reagents, catalog number 237) were propagated in RPMI 1640 medium (Invitrogen, Carlsbad, CA)

15 containing 10% fetal bovine serum (SFB, Hyclone, Logan, UT)  Virus infection - A single-turn infectious indicator virus was produced by co-transfection of HEK 293T cells with a plasmid expressing the LAI envelope of the HIV-1 together with a plasmid containing an HIV-1 LAI proviral cDNA with the envelope gene replaced by a firefly luciferase indicator gene (Chen et al., Ref. 41). Transfections were performed using lipofectAMINE PLUS reagent as described by the manufacturer (Invitrogen, Carlsbad, CA).

Experimental Procedure

1. MT2 cells were seeded in 384-well black plates, at a cell density of 5 x 103 cells per well in 25 µl of RPMI 1640 containing 10% SFB.

2.

Compound (diluted in dimethylsulfoxide and growth medium) was added to the cells at 12.5 µl / well, so that the final test concentration would be ≤ 50 nM.

3. 12.5 µl of single-round infectious indicator virus was added in the middle of Eagle modified by Dulbecco to the sown and compound cells at an approximate multiplicity of infection (MOI) of 0.01, resulting in a final volume of 50 µl per well.

Four.

Cells infected with the virus were incubated at 37 degrees Celsius in a CO2 incubator and collected 72 h after infection.

5. Viral infection was monitored by measuring luciferase expression in infected cells using a luciferase indicator gene assay kit (Steady-Glo, Promega, Madison, WI) as described by the manufacturer. Then, luciferase activity was quantified by measuring luminescence using an EnVision Multilabel plate reader (PerkinElmer, Waltham, MA).

35 6. The percentage of inhibition for each compound was calculated by quantifying the level of luciferase expression in infected cells in the presence of each compound as a percentage of that observed for infected cells in the absence of compound and subtracting the value determined in this way from 100 .

7. An EC50 provides a method for comparing the antiviral potency of the compounds of the invention. The effective concentration for a fifty percent inhibition (EC50) was calculated with the adjustment software

40 of Microsoft Excel Xlfit curves. For each compound, curves were generated from the percentage of inhibition calculated at 10 different concentrations using a four-parameter logistic model (model 205). The

EC50 data for the compounds are shown in Table 2. Table 1 is the key to the data in Table

2.

Table 1. Biological data key for EC50

Compounds with EC50> 0.5 ° µM Compounds with EC50 <0.5 ° µM Group B

Group A

Table 2

Compound Number

Structure CE50 Table 1 Group

1001

At 0.28 nM

1002

TO

1003

B 691.60 nM

(continuation)

Compound Number

Structure CE50 Table 1 Group

1004

TO

1005

TO

1006

At 95.32 nM

(continuation)

Compound Number

Structure CE50 Table 1 Group

1007

B

1008

B

1009

At 3.72 nM

(continuation)

Compound Number

Structure CE50 Table 1 Group

1010

TO

Claims (5)

1. A compound of Formula I, including pharmaceutically acceptable salts thereof: in which A is selected from the group consisting of: in which a, b, c, d and e are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, COOR56, XR57, NA1A2, C (O) R7, C (O) NR55R56, B, Q and E; B is selected from the group consisting of -C (= NR46) (R47), C (O) NR40R41, aryl, heteroaryl, heteroalicyclic, S (O) 2R8, S (O) 2NR40R41, C (O) R7, XR8a, (C1-6) alkyl -NR40R41, (C1-6) alkyl -COOR8b; in which said aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or of one to three identical or different substituents selected from the group F; in which aryl is naphthyl or phenyl replaced; wherein heteroaryl is a mono or bicyclic system that contains 3 to 7 ring atoms for a monocyclic system and up to 12 atoms in a condensed bicyclic system, including 1 to 4 heteroatoms; wherein the heteroalicyclic is a 3- to 7-membered cyclic mono ring that may contain 1 to 2 heteroatoms in the main chain of the ring and which may be condensed with a benzene or pyridine ring; Q is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl and (C2-6) alkenyl; in which said (C1-6) alkyl and (C2-6) alkenyl are optionally substituted with one to three same or different halogens or from one to three identical or different substituents selected from the group consisting of C (O) NR55R56, hydroxy, cyano and XR57; E is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl and (C2-6) alkenyl; in which said (C1-6) alkyl and (C2-6) alkenyl are, independently, optionally substituted with a member selected from the group consisting of phenyl, heteroaryl, SMe, SPh, -C (O) NR56R57, C (O) R57, SO2-alkyl (C1-6) and SO2Ph; in which heteroaryl is a monocyclic system containing 3 to 7 ring atoms, including 1 to 4 heteroatoms; F is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, aryloxy, thioalkoxy (C1-6), cyano, halogen, nitro, -C (O) R57, benzyl, -NR42C (O) -alkyl (C1-6), NR42C (O) -C3-6cycloalkyl, -NR42C (O) -aryl, -NR42C (O) -heteroaryl, -NR42C (O) -heteroalicyclic, an N-lactam 4, 5 or 6-membered ring cyclic, -NR42S (O) 2-C1-6 alkyl, -NR42S (O) 2-cycloalkyl (C3-6), -NR42S (O) 2-aryl, NR42S ( O) 2-heteroaryl, -NR42S (O) 2-heteroalicyclic, S (O) 2-alkyl (C1-6), S (O) 2aryl, -S (O) 2 NR42R43, NR42R43, (C1-6) -C (O) NR42R43, C (O) NR42R43, NHC (O) NR42R43, OC (O) NR42R43, NHC (O) OR54, (C1-6) -NR42R43 alkyl, COOR54 and (C1-6) alkyl -COOR54; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, (C1-6) alkoxy and aryloxy, are optionally substituted with one to nine equal or different halogens or from one to five identical or different substituents selected from group G; in which aryl is phenyl; heteroaryl is a monocyclic system containing 3 to 7 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; G is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, aryloxy, cyano, halogen, nitro, -C (O) R57, benzyl, -NR48C (O) -alkyl (C1-6), -NR48C (O) cycloalkyl (C3-6) , -NR48C (O) -aryl, -NR48C (O) -heteroaryl, -NR48C (O) -heteroalicyclic, a 4, 5 or 6-membered ring cyclic N-lactam, -NR48S (O) 2-alkyl (C1 -6), -NR48S (O) 2-cycloalkyl (C3-6), -NR48S (O) 2-aryl, NR48S (O) 2-heteroaryl, -NR48S (O) 2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR48R49, alkyl (C1-6) C (O) NR48R49, C (O) NR48R49, NHC (O) NR48R49, OC (O) NR48R49, NHC (O) OR54, alkyl (C1-6) -NR48R49, COOR54 and alkyl (C1-6) -COOR54; in which aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; R7 is selected from the group consisting of (C1-6) alkyl, (C2-6) alkenyl, (C3-7) cycloalkyl, aryl, heteroaryl and heteroalicyclic; wherein said aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or with one to three same or different substituents selected from the group F; wherein for R7, R8, R8a, R8b aryl is phenyl; heteroaryl is a mono or bicyclic system that contains 3 to 7 ring atoms for monocyclic systems and up to 10 atoms in a bicyclic system, including 1 to 4 heteroatoms; wherein heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; R8 is selected from the group consisting of hydrogen, (C1-6) alkyl, cycloalkyl (C3-7), alkenyl (C2-6), cycloalkenyl (C3-7), alkynyl (C2-6), aryl, heteroaryl and heteroalicyclic; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, (C2-6) alkenyl, (C3-7) cycloalkenyl, (C2-6) alkynyl, aryl, heteroaryl and heteroalicyclic optionally is substituted with one to six equal or different halogens or one to five identical or different substituents selected from the group F or (C1-6) alkyl, cycloalkyl (C3-6), cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-) alkoxy 6), halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate , sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl; R8a is a member selected from the group consisting of aryl, heteroaryl and heteroalicyclic; wherein each member is optionally independently substituted with one to six same or different halogens or from one to five identical or different substituents selected from the group F; R8b is selected from the group consisting of hydrogen, (C1-6) alkyl and phenyl; X is selected from the group consisting of NH or NCH3, O and S; R40 and R41 are independently selected from the group consisting of (a) hydrogen; (b) (C1-6) alkyl or (C3-7) cycloalkyl substituted with one to three same or different halogens or one to two same or different substituents selected from the group F or different functional groups: (C1-6) alkyl , C3-6 cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, C1-6 alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfonamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine , peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl; and (c) (C1-6) alkoxy, aryl, heteroaryl or heteroalicyclic; or R40 and R41 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine and morpholine; and wherein said aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or one to two same or different substituents selected from the group F; in which for R40 and R41 aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 6 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; provided that when B is C (O) NR40R41, at least one of R40 and R41 is not selected from groups (a) or (b); R42 and R43 are independently selected from the group consisting of hydrogen, (C1-6) alkyl, allyl, (C1-6) alkoxy, (C3-7) cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R42 and R43 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine and morpholine; and wherein said (C1-6) alkyl, (C1-6) alkoxy, (C3-7) cycloalkyl, aryl, heteroaryl and heteroalicyclic acid are optionally substituted with one to three same or different halogens or one to two equal substituents or different selected from group G or different functional groups: (C1-6) alkyl, (C3-6) cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, halogen, benzyl, primary amine , secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl; in which for R42 and R43 aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 6 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; R46 is selected from the group consisting of H, phenyl, aryl, heteroaryl and (C1-6) alkyl, OR57 and NR55R56; R47 is selected from the group consisting of H, amino, hydroxyl, phenyl, aryl, heteroaryl and (C1-6) alkyl; R48 and R49 are independently selected from the group consisting of hydrogen, (C1-6) alkyl, phenyl, aryl and heteroaryl; R50 is selected from the group consisting of H, (C1-6) alkyl, (C3-6) cycloalkyl and benzyl; in which each of said (C1-6) alkyl, (C3-7) cycloalkyl and benzyl are optionally substituted with one to three (C1-6) alkyl, (C3-6) cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, halogen, benzyl, amine primary, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfonamide, acyl sulfonamide, sulfate, sulfuric acid, acid sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, the same or different, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl R54 is selected from the group consisting of hydrogen and (C1-6) alkyl; R54 'is (C1-6) alkyl; R55 and R56 are independently selected from the group consisting of hydrogen and (C1-6) alkyl; and R57 is selected from the group consisting of hydrogen, (C1-6) alkyl, aryl, heteroaryl; Y A1 and A2 are independently selected from hydrogen, (C1-6) alkyl, aryl, heteroaryl, SO2D1, SO2ND2D3, COD4, COCOD4, COOD4, COND5D6, COCOND5D6, COCOOD4, C (= ND7) D8, C (= ND9) ND10D11; A1 and A2 can either connect to each other or join to form a ring structure; D1, D2, D3, D4, D5, D6, D7, D8, D9, D10 and D11 are each independently selected from the group that consists of H, C1-C50 alkyl, C3-C50 cycloalkyl, C3-C50 alkenyl, C4-C50 cycloalkenyl, phenyl, heteroaryl, amide C3-C50 and C3-C50 ether; heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo [4,5-b] pyridin-2-yl, 1H-imidazo [4,5-c] pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl; provided that the carbon atoms comprising double carbon-carbon bond of said C3-C20 alkenyl or the carbon-carbon triple bond of said C3-C20 alkynyl not be the point of union with the nitrogen to which D2, D3, D5, D6, D7, D9, D10 and D11 bind; in which said alkyl C1-C50, C3-C50 cycloalkyl, C3-C50 alkenyl, C4-C50 cycloalkenyl, aryl, phenyl, heteroaryl, C3-C50 amide and ether C3-C50 are optionally substituted with one to three of the following functionalities, the same or different: (C1-6) alkyl, (C3-6) cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfonamide, acyl sulfonamide, sulfate, acid sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide and steroids, among which ether, peroxide, thioether, secondary amine, amine tertiary, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; Z is selected from the group consisting of: I1, I2, I3, I4, I5, I6, I7 and I8 are each independently selected from the group consisting of H, halogen, (C 1-6) alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 4-6 cycloalkenyl, C 2-6 alkynyl, CR81R82OR83, COR84, COOR85 or CONR86R87; wherein each of said alkyl and cycloalkyl is optionally substituted with one to three cyano, phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C 1-6) alkoxy, halogen, benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfonamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, same or different, among which ether, peroxide, thioether, secondary amine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be acyclic or cyclic; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl; R81, R82, R83, R84, R85, R86 and R87 are each independently selected from the group consisting of H, (C1-6) alkyl, (C3-6) cycloalkyl, (C2-6) alkenyl, (C4-6) cycloalkenyl, (C2-6) alkynyl; L is a chain containing 1-20 groups selected from the group consisting of C (B1) (B2), O, NR3, S, S (O), S (O2), C (O) O, C (O) NA1, OC (O) NA1, NA1C (O) NA1 and Group D, provided that O, S (O), S (O2) and C (O) O do not join directly with each other; B1 and B2 are independently selected from the group consisting of hydrogen, (C1-6) alkyl, cycloalkyl (C3-7), aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, aryloxy, thioalkoxy (C1-6) ), cyano, halogen, nitro, C (O) R57, benzyl, -NR42C (O) -alkyl (C1-6), -NR42C (O) -cycloalkyl (C3-6), -NR42C (O) -aryl, -NR42C (O) -heteroaryl, NR42C (O) -heteroalicyclic, a cyclic N-lactam of 4, 5 or 6 members, -NR42S (O) 2-alkyl (C1-6), -NR42S (O) 2-cycloalkyl (C3 -6), -NR42S (O) 2-aryl, -NR42S (O) 2-heteroaryl, -NR42S (O) 2-heteroalicyclic, S (O) 2-alkyl (C1-6), S (O) 2-aryl, -S (O) 2 NR42R43, NR42R42, (C1-6) alkyl -C (O) NR42R43, C (O) NR42R43, NHC (O) NR42R43, OC (O) NR42R43, NHC (O) OR54, alkyl (C1 -6) -NR42R43, COOR54 and (C1-6) alkyl -COOR54; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, (C1-6) alkoxy and aryloxy optionally are substituted with one to nine equal or different halogens or one to five substituents same or different selected from group G; in which aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; Ar1 and Ar2 are selected from the group consisting of phenyl and heteroaryl; wherein said phenyl and heteroaryl are, independently, optionally substituted with one to three same or different halogens or one to three same or different substituents selected from Group C; heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo [4,5-b] pyridinin -yl, 1H-imidazo [4,5c] pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl; Group C is selected from the group consisting of OH, OR8, NA1A2, CN, COOR8, CONA1A2, SO2R8, SO2NA1A2, alkyl (C1-C4), cycloalkyl (C3-C6) and group D; and wherein said alkyl or cycloalkyl group is optionally substituted with one to three substitutions selected from the group of F, OH, OR8, NA1A2, COOR8, CONA1A2, SO2R8, SO2NA1A2; and Group D is selected from the group consisting of phenyl and heteroaryl; wherein said phenyl and heteroaryl are, independently, optionally substituted with one to three same or different halogens or one to three same or different substituents selected from Group C; heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo [4,5-b] pyridinin -yl, 1H-imidazo [4,5c] pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl that is different from 2. A compound according to claim 1, including pharmaceutically acceptable salts thereof, which is selected from the group of: 3. A compound according to claim 1, including pharmaceutically acceptable salts thereof, which is selected from the group: A pharmaceutical composition comprising an effective antiviral amount of one or more of the compounds of Formula I according to any one of claims 1 to 3, together with one or more pharmaceutically acceptable carriers, excipients and / or diluents. 5. The pharmaceutical composition of claim 4, useful for the treatment of HIV infection, which it further comprises an effective antiviral amount of an AIDS treatment agent selected from the group consisting of:

(to)

an antiviral agent against AIDS;

(b)

an anti-infective agent;

(C)

an immunomodulator; Y

(d)

another inhibitor of HIV entry.

A compound of any one of claims 1 to 3, for use in a method of treating a mammal infected with the HIV virus, wherein the compound is administered with one or more vehicles, excipients and / or diluents. pharmaceutically acceptable. 7. A compound for use according to claim 6, wherein the compound is administered in combination with an effective antiviral amount of an AIDS treatment agent selected from the group that 20 consists of an antiviral agent against AIDS; an anti-infective agent; an immunomodulator; and another inhibitor of HIV entry.